Evan syndrome as initial presentation of COVID-19 infection

Background Evans’ syndrome (ES) is a rare and chronic autoimmune disease characterized by the concomitant or sequential association of auto-immune hemolytic anemia (AIHA) with immune thrombocytopenia (ITP), and less frequently autoimmune neutropenia with a positive direct anti-human globulin test. ES represents up to 7% of AIHA and around 2% of ITP. Studies have found that coronavirus disease 2019 (COVID-19) may be associated with various hematological complications, i.e., coagulopathies; however, finding of Evans syndrome is a novel case. Case report A 54-year-old diabetic man complaining of fever (high grade), arthralgia and myalgia, fatigue, and dark color of urine. He was admitted to isolation sector at Sohag General Hospital on day 6 because of fever with cough, dyspnea, and progressive fatigue, and at admission, he was tachypneic, tachycardiac, jaundiced, febrile (38 °C), and hypoxemic (O2 saturations on room air was 80%). Laboratory studies showed hemoglobin (Hb) 5.43 g/dL, high reticulocyte (12.5%), ↓ed platelet count (54 × 103/μl), hyperbilirubinemia and elevated C-reactive protein (CRP), D-dimer, ferritin, and lactate dehydrogenase. Markers of autoimmune diseases and screening for malignant diseases were negative. HRCT chest showed bilateral small-sized peripheral ground glass opacities in both lungs, with positive reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA in the nasopharyngeal swab. Direct Coombs test was positive for immunoglobulin (IgG) and C3d. Evans syndrome secondary to COVID-19 was diagnosed and treatment with packed red cell (PRC) transfusions, favipiravir, dexamethasone, prednisone, ceftriaxone, enoxaparin, oral hypoglycemic, and oxygen using face mask, and then Hb value increased to 10.3 g/dL and he was discharged home without any complications. Conclusion There are few reports of patients with concurrent COVID-19 and Evans syndrome. So, SARS-CoV-2 infection should be considered in any patient presenting with new-onset ES of unclear etiology.


Introduction
Evans syndrome (ES), which was first described in 1951, is an autoimmune disorder characterized by the development of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) and/or immune neutropenia simultaneously or consecutively in the absence of any underlying cause [1]. The precise pathophysiology is not entirely understood; it is believed that dysregulation of the immune system is a primary contributor to the condition. It is classified as primary and secondary. Primary Evans syndrome with no cause is very rare and is seen in children. Secondary Evans syndrome may be associated with or show other diseases or conditions such as autoimmune disorders, lymphoproliferative disorders, or primary immunodeficiencies [2], viral infections including hepatitis C, cytomegalovirus, varicella-zoster, and Epstein-Barr viruses [3,4]. ES is one of the rare presenting features of autoimmune disorders, especially systemic lupus erythematosus (SLE). Evans syndrome occurs in patients with severe multisystem SLE manifestations and sometimes may even precede the onset of disease [5]. ES is a rare condition because it is diagnosed in only 0.8 to 3.7% of all patients with either ITP or AIHA at onset. The clinical features include fatigue, pallor, jaundice, ecchymosis, petechiae, gingivorrhagia, epistaxis and mucosal bleeding, with remissions and exacerbations during the person's lifetime, and acute manifestations as catastrophic bleeding and massive hemolysis [6]. As in other autoimmune cytopenias, there is no established evidence-based treatment and steroids are the first-line therapy, with intravenous immunoglobulin administered as a life-saving resource in cases of severe immune thrombocytopenic purpura manifestations. Second-line treatment for refractory ES includes rituximab, mofetil mycophenolate, cyclosporine, vincristine, azathioprine, sirolimus, and thrombopoietin receptor agonists. In cases unresponsive to immunosuppressive agents, hematopoietic stem cell transplantation has been successful, although it is necessary to consider its potential serious adverse effects [7,8]. Coronavirus disease 2019 (COVID- 19) is an infection caused by severe acute respiratory syndrome coronavirus 2 (SARSCOV-2). Although acute respiratory distress syndrome (ARDS), cardiac complications, and thromboembolic events have contributed to majority of the disease mortality, it has been suggested that this infection has several hematological abnormalities that develop after or concomitantly to COVID-19 infection [9] and include reduced numbers of peripheral blood lymphocytes (lymphopenia) and eosinophils with an increased polymorphonuclear-to-lymphocyte ratio, autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), Evans syndrome, autoimmune neutropenia, thrombotic thrombocytopenic purpura (TTP), antiphospholipid syndrome, coagulopathies, including disseminated intravascular coagulation, and increased ferritin and d-dimer levels [10,11].

Discussion
Evans syndrome (ES) is a rare condition characterized by the combination of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) [8]. Evans syndrome seems to be a disorder of immune regulation but the exact pathophysiology is unknown. Autoantibodies targeted at different antigenic determinants on red cells and platelets leading to the development of autoimmune hemolytic anemia (AIHA) and immunethrombocytopenia (ITP). Those causing red blood cell (RBC) destruction are directed against a base protein portion of the Rh blood group, while those that destroy platelets are frequently directed against platelet GPIIb/IIIa [19]. The pathogenesis and management of ES in the setting of the inflammatory milieu of COVID-19 has not been previously described and represents a unique challenge in clinical management. The exact pathophysiology of ES is not fully elucidated, but studies suggest the intersection of autoimmunity and predisposing immune dysregulation is involved. Several proposed mechanisms of autoimmunity have been described, including activation of Bruton tyrosine kinase and overexpression of cytokines [20].
Various viral infections are known to cause ES, hepatitis C virus (HCV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Varicella Zoster Virus (VZV) [8]. More recently, SARS-CoV-2 has been reported as a potential cause of ES [11] and Li et al. [12] reported the first case of COVID-19-associated ES. This 38-year-old male patient had presented with evidence of immune hemolysis 4 days after being discharged with demonstration of a complete platelet response to treatment of ITP. Demir et al. [15] reported the second in the literature case of 22-year-old male patient presented with AIHA and grade IV thrombocytopenia, the patient was diagnosed with SARS-CoV-2-associated ES. Our patient is similar to Demir et al. [15] but differs from Li et al. [12]; the first with regard to both clinical findings and treatment method. Our patient developed AIHA first and then immune thrombocytopenia, like in case of Demir et al. [15],whereas in the case of Li et al. [12], first immune thrombocytopenia and then AIHA emerged 1 week after. Another difference between the cases was that hemoglobin level in case of Demir et al. [15] was as low as 3.9 g/dL at the time of admission to the hospital despite the absence of active bleeding, so multiple erythrocyte transfusions were needed to try to increase his hemoglobin concentration. Also, Zarza et al. [16] found a case of COVID-19 associated with Evans syndrome (hemolytic anemia plus thrombocytopenia, both with autoimmune causes) and antiphospholipid antibodies.
Other autoimmune disorders associated with COVID-19 include immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) [21]. COVID-19 has been identified as a causal factor of ITP in a 65-yearold woman with HTA and autoimmune hypothyroidism [22]. Other authors described the first case series of 3 patients with ITP associated with COVID-19 [23]. Lazarian et al. [10] reported seven cases of warm and cold AIHA associated with COVID-19. These cases occurred during the course of the disease earlier (i.e., a median of 9 days) after admission. However, an indolent B cell malignancy was present in four of them, all required treatment with either steroids or transfusion. Furthermore, another case of AIHA during COVID-19 was reported in a 46-year-old female with a medical history of congenital thrombocytopenia [24]. Several other hematologic disorders have been associated with COVID-19 such as cold agglutinin syndrome, Evans syndrome, or autoimmune thrombotic thrombocytopenic purpura [25,26]. The structural similarity between an erythrocyte membrane protein named ANK-1 and the viral protein spike led Angileri et al. to postulate that molecular mimicry could contribute to the pathogenesis of COVID-19-associated AIHA [27].
Barcellini et al. [17] reported 4 patients with autoimmune cytopenias (AIC) (2 autoimmune hemolytic anemias, AIHA, 1 Evans syndrome, and 1 immune thrombocytopenia) with COVID-19 pneumonia. Most of COVID-related cytopenias described in literature        developed at the time of COVID-19 infection (generally within the first month). It is largely known that autoimmune cytopenias may be triggered by viral and bacterial infections, due to mechanisms of molecular mimicry, hidden epitope spreading and neo-antigen generation [2,28]. Interestingly, the RBC membrane protein ankyrin-1 was found to share a 100% identity with the SARS-CoV-2 surface glycoprotein spike [27], suggesting a molecular mimicry mechanism for AIHA. Regarding ITP, anti-GP IIb/IIIa, GP-Ib/IX, or GP-V antibodies have been identified in several cases [29], although a sequence homology between platelet components and SARS-CoV-2 still needs to be documented. Furthermore, during infections, platelets and viruses interact in a sialic acid-dependent manner, leading to increased hepatic clearance of platelets. Sialic acids may act as additional receptors for SARS-COV-2 spike protein, possibly accounting for thrombocytopenia in COVID-19, as observed for influenza virus [30,31]. Finally, AIC secondary to infections are thought to be often transient and/or promptly responsive to first-line therapy.
Wahlster et al. [13] report case of a17-year-old male patient with SARS-CoV-2 infection and underlying immune dysregulation subsequently found to have ES. The onset of this patient's COVID-19 infection was unknown; however, preexisting COVID-19 infection leading to widespread immune activation prior to her initial admission may have served as a trigger for the new onset of ES.
Vadlamudi et al. [32] reported that a 23-year-old multigravida woman in active labor was found to have severe anemia and thrombocytopenia. She was diagnosed with ES and started on immunosuppressive treatments for persistent immune thrombocytopenic purpura. In the postpartum period, she was found to have coronavirus (COVID-19) infection and acute pulmonary embolism.
Georgy et al. [18] demonstrate a 33-year-old man presented with a 3-week history of gum bleeding, black tarry stools, and reddish spots on the skin, no fever, cough, or dyspnea, with petechial lesions over the chest, legs, and oral mucosa. There was severe thrombocytopenia (6 × 109/L), anemia (7.5 g/dl), elevated lactate dehydrogenase (1953 U/L). Total and direct bilirubin were {1.23 and 0.46}, reticulocyte count was (13.73%). Direct Coombs test was positive (2+), suggesting immune hemolytic anemia. Within a few hours of admission, the patient complained of sudden-onset headache and developed a generalized tonic-clonic seizure. CT of the brain showed intracerebral hemorrhage in the right capsuloganglionic region with edema and midline shift. The patient's sensorium worsened rapidly with anisocoria, and he was shifted to the intensive care unit. (RT-PCR) for SARS-CoV-2 was positive. There was no improvement in the patient's platelet counts, nor sensorium, and he died on the third day of admission.
Sahu et al. [33] found on their literature search 20 patients with COVID-19 who were reported to have immune dysregulation with the development of ITP, AIHA, and/or Evan's syndrome. There were 10 (50%) patients with ITP, 9 (45%) patients with AIHA, and 1 (5%) patient had Evan's syndrome. The average age of the patients was 61 (17-89 years) years with the majority (55%) being males (11 out of 20 The management of Evans syndrome remains a challenge. There is no therapeutic regimen established. Steroids with and without intravenous immunoglobulin (IVIG) are recommended as first-line therapy and administered as a life-saving resource in cases of severe immune thrombocytopenic purpura manifestations. The American Society of Hematology guideline [34] recommends dexamethasone (40 mg/day for 4 days) or prednisolone (1 mg/kg/day) with tapering (depending on response and for a maximum duration of 6 weeks, red blood cell/ platelet transfusion is indicated only in severe symptomatic patients. Second-line treatment for refractory ES includes rituximab, cyclophosphamide, mycophenolate mofetil, cyclosporine, vincristine, azathioprine, sirolimus, splenectomy, and thrombopoietin receptor agonists. In cases unresponsive to immunosuppressive agents, hematopoietic stem cell transplantation has been successful. Anticoagulation thromboprophylaxis with low molecular weight heparin is recommended for inpatients with acute exacerbation. This will be stopped if platelet count˂ 50 G/L [32].
The treatment of AIHA or ES during an infection is difficult and may be best individualized according to the patient's characteristics. By sharing our experiences, as the data in the literature increase, it may become easier to make the most beneficial treatment decisions for the patient [15].
To the best of our knowledge, this is the first case report of COVID-19 infection with Evans syndrome in Egypt. In another case report, seven patients from hospitals in